Chromosome 10q26-driven age-related macular degeneration is associated with reduced levels of HTRA1 in human retinal pigment epithelium.

Abstract

Genome-wide association studies have identified the chromosome 10q26 (Chr10) locus, which contains the age-related maculopathy susceptibility 2 (ARMS2) and high temperature requirement A serine peptidase 1 (HTRA1) genes, as the strongest genetic risk factor for age-related macular degeneration (AMD) [L.G. Fritsche et al., Annu. Rev. Genomics Hum. Genet. 15, 151-171, (2014)]. To date, it has been difficult to assign causality to any specific single nucleotide polymorphism (SNP), haplotype, or gene within this region because of high linkage disequilibrium among the disease-associated variants [J. Jakobsdottir et al. Am. J. Hum. Genet. 77, 389-407 (2005); A. Rivera et al. Hum. Mol. Genet. 14, 3227-3236 (2005)]. Here, we show that HTRA1 messenger RNA (mRNA) is reduced in retinal pigment epithelium (RPE) but not in neural retina or choroid tissues derived from human donors with homozygous risk at the 10q26 locus. This tissue-specific decrease is mediated by the presence of a noncoding, cis-regulatory element overlapping the ARMS2 intron, which contains a potential Lhx2 transcription factor binding site that is disrupted by risk variant rs36212733. HtrA1 protein increases with age in the RPE-Bruch's membrane (BM) interface in Chr10 nonrisk donors but fails to increase in donors with homozygous risk at the 10q26 locus. We propose that HtrA1, an extracellular chaperone and serine protease, functions to maintain the optimal integrity of the RPE-BM interface during the aging process and that reduced expression of HTRA1 mRNA and protein in Chr10 risk donors impairs this protective function, leading to increased risk of AMD pathogenesis. HtrA1 augmentation, not inhibition, in high-risk patients should be considered as a potential therapy for AMD.

• Authors: Brandi L Williams, Nathan A Seager, Jamie D Gardiner, Chris M Pappas, Monica C Cronin, Cristina Amat di San Filippo, Robert A Anstadt, Jin Liu, Marc A Toso, Lisa Nichols, Timothy J Parnell, Jacqueline R Eve, Sven Heinz, Michael G B Hayes, Paul L Bartel, Moussa A Zouache, Burt T Richards, Gregory S Hageman
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 118 Issue 30 (07 27 2021) ISSN: 1091-6490 [Electronic] United States
• PMID: 34301870 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 the Author(s). Published by PNAS.

Chemical References

• RNA, Messenger
• High-Temperature Requirement A Serine Peptidase 1
• HtrA1 protein, human

Topics

• Choroid (metabolism)
• Genetic Predisposition to Disease
• Genetic Variation
• High-Temperature Requirement A Serine Peptidase 1 (genetics, metabolism)
• Humans
• Linkage Disequilibrium
• Macular Degeneration (genetics)
• RNA, Messenger (genetics, metabolism)
• Retina (metabolism)
• Retinal Pigment Epithelium (metabolism)